Optically active 1-(fluoro-, trifluoromethyl-or trifluoromethoxy-substituted phenyl) alkylamine n-monoalkyl derivatives and process for producing same

Abstract

An optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl derivative represented by the formula 4 is produced by a process including (a) reacting an optically active secondary amine, represented by the formula 1, with an alkylation agent R<SUP>2</SUP>-X, in the presence of a base, thereby converting the secondary amine into an optically active tertiary amine represented by the formula 3; and (b) subjecting the tertiary amine to a hydrogenolysis, thereby producing the N-monoalkyl derivative, wherein R represents a fluorine atom, trifluoromethyl group or trifluoromethoxy group, n represents an integer of from 1 to 5, each of R<SUP>1 </SUP>and R<SUP>2 </SUP>independently represents an alkyl group having a carbon atom number of from 1 to 6, Me represents a methyl group, Ar represents a phenyl group or 1- or 2-naphthyl group, * represents a chiral carbon, and X represents a leaving group.

The invention claimed is:  
     
       1. A process for producing an optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl derivative represented by the formula 4, the process comprising the steps of:
 (a) reacting an optically active secondary amine, represented by the formula 1, with an alkylation agent represented by the formula 2, in the presence of a base, thereby converting the secondary amine into an optically active tertiary amine represented by the formula 3; and 
 (b) subjecting the tertiary amine to a hydrogenolysis, thereby producing the N-monoalkyl derivative, 
 
       
         
           
           
               
               
           
         
         wherein R represents a fluorine atom, trifluoromethyl group or trifluoromethoxy group, 
         n represents an integer of from 1 to 5, 
         R 1  represents an alkyl group having a carbon atom number of from 1 to 6,
 Me represents a methyl group, 
 
         Ar represents a phenyl group or 1- or 2-naphthyl group, and 
         * represents a chiral carbon,
   R 2 —X  [2]
 
 
         wherein R 2  represents an alkyl group having a carbon atom number of from 1 to 6, and X represents a leaving group, 
       
       
         
           
           
               
               
           
         
         wherein R, n, R 1 , Me, Ar, and * are defined as in the formula 1, and R 2  is defined as in the formula 2, 
       
       
         
           
           
               
               
           
         
         wherein R, n, R 1 , and * are defined as in the formula 1, and R 2  is defined as in the formula 2. 
       
     
     
       2. A process according to  claim 1 , wherein the secondary amine of the step (a) is produced by a process comprising the steps of:
 (c) reacting a fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl alkyl ketone, represented by the formula 5, with an optically active primary amine represented by the formula 6 under an acidic condition to achieve dehydration and condensation, thereby producing an optically active imine represented by the formula 7; and 
 (d) asymmetrically reducing the imine by a hydride reducing agent into the secondary amine, 
 
       
         
           
           
               
               
           
         
         wherein R, n and R 1  are defined as in the formula 1, 
       
       
         
           
           
               
               
           
         
         wherein Me, Ar and * are defined as in the formula 1, 
       
       
         
           
           
               
               
           
         
         wherein R, n, R 1 , Me, Ar and * are defined as in the formula 1, and a wave line in the formula 7 indicates that the imine is in an E configuration or Z configuration. 
       
     
     
       3. A process according to  claim 1 , wherein Ar of the general formula 1 is a phenyl group. 
     
     
       4. A process according to  claim 2 , wherein the optically active primary amine of the step (c) has an enantiomeric excess of 98% ee or greater. 
     
     
       5. A process according to  claim 2 , wherein the step (c) is conducted in the presence of an acid catalyst to make the acidic condition. 
     
     
       6. A process according to  claim 5 , wherein the acid catalyst is p-toluenesulfonic acid or zinc chloride. 
     
     
       7. A process according to  claim 2 , wherein the step (c) is conducted in a reaction solvent under a reflux, while water as a by-product of the step (c) is removed from a reaction system of the step (c), and
 wherein the reaction solvent of the step (c) is immiscible with water, has a specific gravity that is less than that of water, and forms an azeotropic mixture with water. 
 
     
     
       8. A process according to  claim 7 , wherein the reaction solvent of the step (c) is an aromatic hydrocarbon selected from the group consisting of benzene, toluene, ethylbenzene, xylene, and mesitylene. 
     
     
       9. A process according to  claim 8 , wherein the reaction solvent of the step (c) is toluene. 
     
     
       10. A process according to  claim 2 , wherein the hydride reducing agent is selected from the group consisting of LiAlH 4 , diborane, NaBH 4 , and LiBH 4 . 
     
     
       11. A process according to  claim 2 , wherein the step (d) is conducted in a reaction solvent that is at least one selected from the group consisting of tetrahydrofuran, methanol, ethanol, and i-propanol. 
     
     
       12. A process according to  claim 2 , wherein the secondary amine obtained by the step (d) is improved in diastereomeric excess by a process comprising the steps of:
 (e) converting the secondary amine into a salt of an inorganic acid or organic acid; and 
 (f) subjecting the salt to a recrystallization. 
 
     
     
       13. A process according to  claim 12 , wherein the organic acid of the step (e) is selected from the group consisting of fumaric acid, phthalic acid, and p-toluenesulfonic acid. 
     
     
       14. A process according to  claim 12 , wherein the step (f) is conducted in a recrystallization solvent that is at least one selected from the group consisting of n-hexane, n-heptane, toluene, methylene chloride, t-butyl methyl ether, acetone, ethyl acetate, acetonitrile, methanol, ethanol, n-propanol, and i-propanol. 
     
     
       15. A process according to  claim 12 , wherein the step (f) is conducted in the presence of seed crystals of the salt. 
     
     
       16. A process according to  claim 1 , wherein X of the formula 2 is selected from the group consisting of bromine, iodine, mesylate group, tosylate group, and triflate group. 
     
     
       17. A process according to  claim 16 , wherein X of the formula 2 is selected from the group consisting of bromine, iodine, and mesylate group. 
     
     
       18. A process according to  claim 1 , wherein the base of the step (a) is at least one selected from the group consisting of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2,6-lutidine, sodium hydride, sodium carbonate, and potassium carbonate. 
     
     
       19. A process according to  claim 1 , wherein the step (a) is conducted in a reaction solvent that is at least one selected from the group consisting of tetrahydrofuran, N, N- dimethylformamide, N,N-dimethylacetamide, acetonitrile, and dimethylsulfoxide. 
     
     
       20. A process according to  claim 1 , wherein the step (b) is conducted in the presence of a catalyst comprising a transition metal that is in a form of element or compound. 
     
     
       21. A process according to  claim 20 , wherein the transition metal is selected from the group consisting of platinum, rhodium, and palladium, and wherein the transition metal is carried on an activated carbon as a carrier of the catalyst. 
     
     
       22. A process according to  claim 1 , wherein the step (b) is conducted in the presence of an additive that is selected from the group consisting of acetic acid, hydrochloric acid, and sulfuric acid. 
     
     
       23. A process according to  claim 1 , wherein the step (b) is conducted in a reaction solvent that is at least one selected from the group consisting of methanol, ethanol, i-propanol, an acetic acid, and a hydrochloric acid aqueous solution.